title: Induced hypothermia in severe bacterial meningitis: a randomized clinical trial.
abstract: OBJECTIVE
  Despite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia.
  
  
  OBJECTIVE
  To test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis.
  
  
  METHODS
  An open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009-November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for <12 hours) with community-acquired bacterial meningitis were randomized.
  
  
  METHODS
  Hypothermia group received a loading dose of 4°C cold saline and were cooled to 32°C to 34°C for 48 hours. The rewarming phase was passive. Controls received standard care.
  
  
  METHODS
  Primary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients.
  
  
  RESULTS
  After inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; P = .04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3°C (0.9°C) and 37.0°C (0.9°C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; P = .13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; P = .10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977).
  
  
  CONCLUSIONS
  Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00774631.
authors.affiliation: Réanimation Médicale et Infectieuse, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Bichat-Claude Bernard, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Bruno
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authors.lastname: Mourvillier
authors.forename: Florence
authors.initials: F
authors.lastname: Tubach
authors.forename: Diederik
authors.initials: D
authors.lastname: van de Beek
authors.forename: Denis
authors.initials: D
authors.lastname: Garot
authors.forename: Nicolas
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authors.lastname: Pichon
authors.forename: Hugues
authors.initials: H
authors.lastname: Georges
authors.forename: Laurent Martin
authors.initials: LM
authors.lastname: Lefevre
authors.forename: Pierre-Edouard
authors.initials: PE
authors.lastname: Bollaert
authors.forename: Thierry
authors.initials: T
authors.lastname: Boulain
authors.forename: David
authors.initials: D
authors.lastname: Luis
authors.forename: Alain
authors.initials: A
authors.lastname: Cariou
authors.forename: Patrick
authors.initials: P
authors.lastname: Girardie
authors.forename: Riad
authors.initials: R
authors.lastname: Chelha
authors.forename: Bruno
authors.initials: B
authors.lastname: Megarbane
authors.forename: Arnaud
authors.initials: A
authors.lastname: Delahaye
authors.forename: Ludivine
authors.initials: L
authors.lastname: Chalumeau-Lemoine
authors.forename: Stéphane
authors.initials: S
authors.lastname: Legriel
authors.forename: Pascal
authors.initials: P
authors.lastname: Beuret
authors.forename: François
authors.initials: F
authors.lastname: Brivet
authors.forename: Cédric
authors.initials: C
authors.lastname: Bruel
authors.forename: Fabrice
authors.initials: F
authors.lastname: Camou
authors.forename: Delphine
authors.initials: D
authors.lastname: Chatellier
authors.forename: Patrick
authors.initials: P
authors.lastname: Chillet
authors.forename: Bernard
authors.initials: B
authors.lastname: Clair
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Constantin
authors.forename: Alexandre
authors.initials: A
authors.lastname: Duguet
authors.forename: Richard
authors.initials: R
authors.lastname: Galliot
authors.forename: Frédérique
authors.initials: F
authors.lastname: Bayle
authors.forename: Hervé
authors.initials: H
authors.lastname: Hyvernat
authors.forename: Kader
authors.initials: K
authors.lastname: Ouchenir
authors.forename: Gaetan
authors.initials: G
authors.lastname: Plantefeve
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Quenot
authors.forename: Jack
authors.initials: J
authors.lastname: Richecoeur
authors.forename: Carole
authors.initials: C
authors.lastname: Schwebel
authors.forename: Michel
authors.initials: M
authors.lastname: Sirodot
authors.forename: Marina
authors.initials: M
authors.lastname: Esposito-Farèse
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Tulzo
authors.forename: Michel
authors.initials: M
authors.lastname: Wolff
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001831:Body Temperature; D003128:Coma; D057239:Early Termination of Clinical Trials; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D007036:Hypothermia, Induced / Q000009:adverse effects*; D008297:Male; D008586:Meningitis, Pneumococcal / Q000628:therapy*; D008875:Middle Aged; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents